High-density lipoproteins affect endothelial BMP-signaling by modulating expression of the activin-like kinase receptor 1 and 2.
OBJECTIVE
High-density lipoproteins (HDL) have antiinflammatory effects on the vascular endothelium. Because bone morphogenetic proteins (BMPs) are known to be inflammatory mediators, we examined the effect of HDL on BMP signaling.


RESULTS
Increasing concentrations of HDL progressively enhanced expression of the activin-like kinase receptor (ALK)1 and ALK2 in human aortic endothelial cells as determined by real-time polymerase chain reaction and immunoblotting. Induction of ALK1 was a result of enhanced ALK2 expression as determined by siRNA interference, and was associated with increased levels of vascular endothelial growth factor (VEGF) and matrix Gla protein (MGP). The HDL-induction of ALK2 was dependent on BMP-signaling, and affected coregulation of the ALK2 gene by the homeodomain proteins MSX2, DLX3, and DLX5, as determined by reporter gene assays, siRNA interference, and chromatin immunoprecipitation. Apolipoprotein A-I transgenic mice, known to have high HDL and inhibition of atherogenesis, exhibited similar changes in aortic gene expression as seen in endothelial cells treated with HDL in vitro.


CONCLUSIONS
We conclude that HDL benefits the arterial wall by allowing for enhanced ALK1 and ALK2 signaling, resulting in an increase of VEGF and MGP, essential for endothelial cell survival and prevention of vascular calcification, respectively.
Yao
Yucheng
Y
Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1679, USA.
Shao
Esther S
ES
Jumabay
Medet
M
Shahbazian
Ani
A
Ji
Sheng
S
Boström
Kristina I
KI
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000097568:Matrix Gla Protein
D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D016632:Apolipoprotein A-I; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D008075:Lipoproteins, HDL; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000097568:Matrix Gla Protein; C525809:BMP4 protein, human; C467484:VEGFA protein, human; C425423:ACVR1 protein, human; C425364:ACVRL1 protein, human